Advanced paternal age has been associated with a number of genetic disorders even though little is known about the mechanisms responsible for the production of genetically abnormal children. For example, the increased risk that a woman older than 35 will give birth to a Down Syndrome child has been well documented. The extent to which the age of the father produces genetic anomalies, however, needs further investigation. In the first part of this project, the paternal age-effect will be studied in the C57BL/6 mouse. Male mice that are 6 and 24 months old will be paired (for 4-6 weeks) with 4-month-old female mice of proven fertility. The number of matings and the number of 10-day-old embryos, 20-day-old fetuses, and resorption sites that result will be analyzed. Chromosomal analyses for aneuploidy will be conducted on the 10-day-old embryos; the 20-day-old fetuses will be examined for developmental abnormalities. In vitro and in vivo (artificial insemination) fertilization studies that use fluorescent markers to label spermatozoa will be performed. The results will indicate whether differences exist in the competitive nature of sperm from the two age groups. The ability of morphologically abnormal spermatozoa to fertilize mouse ova will be determined by in vitro fertilization studies. Developing germ cells of aging mice will be evaluated cytogenetically for an increase in abnormal cells. The data will be compared with information about the increase, with age, of morphologically abnormal sperm. In the second part of the project, the number, viability, motility, and morphologic features of spermatozoa from men in six age categories (21-25, 26-30, 31-35, 36-40, 41-45, and 46-50) will be assessed. The zona-free hamster ovum assay will be used to study the capability of the sperm to fertilize ova. Fluorochrome-dyes will be used for labeling the sperm to detect possible differences in sperm capacitation, attachment to the vitelline membrane, penetration of the vitelline membrane, decondensation of the sperm head within the ooplasm, extrusion of the second polar body, and the formation of the male pronucleus. The frequency with which morphologically abnormal spermatozoa come in contact with, and penetrate, hamster ova will be recorded.